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Journal of Pharmaceutical Sciences Jan 2023The crystal structures of four novel dicarboxylic acid salts of ciprofloxacin (CFX) with modified physicochemical properties, prepared by mechanochemical synthesis and...
The crystal structures of four novel dicarboxylic acid salts of ciprofloxacin (CFX) with modified physicochemical properties, prepared by mechanochemical synthesis and solvent crystallization, are reported. A series of dicarboxylic acids of increasing molecular weight was chosen, predicted to interact via a carboxylic acid:secondary amine synthon. These were succinic (SA), glutaric (GA), adipic (AA) and pimelic (PA) acids (4, 5, 6, 7 carbon atoms respectively). Characterized by single crystal and powder X-ray diffraction, Fourier-Transform Infrared Spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy and aqueous solubility measurements, these salts showed distinct physicochemical properties relative to ciprofloxacin base. Searches of the Cambridge Structural Database (CSD) confirmed CFX-SA, CFX-GA, CFX-AA and CFX-PA to be novel crystal structures. Furthermore, the GA salt has substantially higher solubility than the widely available hydrochloride monohydrate salt (CFX-HCl·HO). CFX-SA, CFX-GA and CFX-AA showed minimum inhibitory concentration (MIC) of 0.008 g/L and CFX-PA showed MIC of 0.004 g/L. The prepared CFX salts retained antibacterial activity exhibiting equivalent antimicrobial activity to CFX-HCl·HO. These salts have positive implications for increasing the application of CFX beyond conventional oral formulations and highlight mechanochemical activation as suitable production method.
Topics: Ciprofloxacin; Salts; Dicarboxylic Acids; Calorimetry, Differential Scanning; Solubility; X-Ray Diffraction; Spectroscopy, Fourier Transform Infrared
PubMed: 35948159
DOI: 10.1016/j.xphs.2022.08.008 -
Acta Dermato-venereologica. Supplementum 1989Medium chain length dicarboxylic acids (DA) from C8 to C13 are competitive inhibitors of tyrosinase in vitro. The introduction of electron acceptor groups or electron... (Review)
Review
Medium chain length dicarboxylic acids (DA) from C8 to C13 are competitive inhibitors of tyrosinase in vitro. The introduction of electron acceptor groups or electron donor groups into the 2 and/or the 8 position of the molecule enhances or reduces respectively the inhibitory effects of DA. In addition to tyrosinase, DA can reversibly inhibit thioredoxin reductase, NADPH cytochrome P450 reductase, NADH dehydrogenase, succinic dehydrogenase and H2CoQ-Cytochrome C oxidoreductase. Among DA, azelaic acid (AA, C9 dicarboxylic acid) is extensively used because: 1) it is much cheaper than other DA; 2) it has no apparent toxic or teratogenic or mutagenic effect; 3) when administered perorally to humans, at the same concentrations as the other DA, it reaches much higher serum and urinary concentrations. Serum concentrations and urinary excretion obtained with intravenous or intra-arterial infusions of AA are significantly higher than those achievable by oral administration. Together with AA, variable amounts of its catabolites, mainly pimelic acid, are found in serum and urine, indicating an involvement of mitochondrial beta-oxidative enzymes. Short-lived serum levels of AA follow a single 1 h intravenous infusion, but prolonging the period of infusion with successive doses of similar concentration produces sustained higher levels during the period of administration. These levels are consistent with the concentrations of AA capable of producing a cytotoxic effect on tumoral cells in vitro. AA is capable of crossing the blood-brain barrier: its concentration in the cerebrospinal fluid is normally in the range of 2-5% of the values in the serum.
Topics: Animals; Binding, Competitive; Blood-Brain Barrier; Dicarboxylic Acids; Electron Transport; Humans; Monophenol Monooxygenase
PubMed: 2505463
DOI: 10.2340/00015555143813 -
Applied Microbiology and Biotechnology Feb 2023Efficient transporters are necessary for high concentration and purity of desired products during industrial production. In this study, we explored the mechanism of...
Efficient transporters are necessary for high concentration and purity of desired products during industrial production. In this study, we explored the mechanism of substrate transport and preference of the C4-dicarboxylic acid transporter AoMAE in the fungus Myceliophthora thermophila, and investigated the roles of 18 critical amino acid residues within this process. Among them, the residue Arg78, forming a hydrogen bond network with Arg23, Phe25, Thr74, Leu81, His82, and Glu94 to stabilize the protein conformation, is irreplaceable for the export function of AoMAE. Furthermore, varying the residue at position 100 resulted in changes to the size and shape of the substrate binding pocket, leading to alterations in transport efficiencies of both malic acid and succinic acid. We found that the mutation T100S increased malate production by 68%. Using these insights, we successfully generated an AoMAE variant with mutation T100S and deubiquitination, exhibiting an 81% increase in the selective export activity of malic acid. Simply introducing this version of AoMAE into M. thermophila wild-type strain increased production of malic acid from 1.22 to 54.88 g/L. These findings increase our understanding of the structure-function relationships of organic acid transporters and may accelerate the process of engineering dicarboxylic acid transporters with high efficiency. KEY POINTS: • This is the first systematical analysis of key residues of a malate transporter in fungi. • Protein engineering of AoMAE led to 81% increase of malate export activity. • Arg78 was essential for the normal function of AoMAE in M. thermophila. • Substitution of Thr100 affected export efficiency and substrate selectivity of AoMAE.
Topics: Malates; Dicarboxylic Acid Transporters; Dicarboxylic Acids
PubMed: 36542100
DOI: 10.1007/s00253-022-12336-9 -
Food Chemistry Sep 2022Dicarboxylic acids derived acylated-anthocyanins are common in nature, which can also be obtained by enzymatic acylation of anthocyanins. However, little research have...
Dicarboxylic acids derived acylated-anthocyanins are common in nature, which can also be obtained by enzymatic acylation of anthocyanins. However, little research have focused on the properties of anthocyanins with dicarboxylic acid derivatives due to the complexity of isolation, detection, and identification. In this work, pelargonidin-3-glucoside (Pg3G) was acylated with various dicarboxylic acids. The conversion yields of acylated Pg3G were positively associated with carbon chain lengths of dicarboxylic acids. The primary acylated products were identified as pelargonidin-3-(6″-malonyl) glucoside, pelargonidin-3-(6″-succinyl) glucoside, and pelargonidin-3-(6″-glutaryl) glucoside using LC-MS and NMR. Furthermore, the three acylated Pg3G derivatives exhibited improved thermostability and enhanced lipophilicity compared with Pg3G. The improved thermostability was attributed to the influence of dicarboxylic acids substituent on the distribution of flavylium cation, quinoidal base, hemiketal, cis-chalcone, and trans-chalcone at the equilibrium condition. Overall, our research provided insights about the improved stability and lipophilicity of pelargonidin-3-glucoside following enzymatic acylation with aliphatic dicarboxylic acids.
Topics: Acylation; Anthocyanins; Chalcones; Dicarboxylic Acids; Fatty Acids; Glucosides
PubMed: 35500410
DOI: 10.1016/j.foodchem.2022.133077 -
Carbohydrate Polymers Jul 2021Carboxylated cellulose nanocrystals (CNCs) were produced from cotton linter using a mixture of a dicarboxylic acid (maleic acid or succinic acid) and its corresponding...
Carboxylated cellulose nanocrystals (CNCs) were produced from cotton linter using a mixture of a dicarboxylic acid (maleic acid or succinic acid) and its corresponding anhydride with or without catalyst in acetic acid as solvent. The low solubilities of these dicarboxylic acids can ease chemical recovery and decrease environmental impact (especailly maleic acid is a U.S. FDA approved indirect food additive (21CFR175-177)) and capital costs compared with the conventional concentrated sulfuric acid hydrolysis for producing CNCs. The dicarboxylic-acid-produced CNCs (DC-CNCs) contained surface carboxyl groups of approximately 0.5 mmol/g, with ranges of dimensions of 50-150 nm in diameter and 50-700 nm in length. Birefringence was observed in the DC-CNC suspensions above critical concentrations. However, fingerprint texture was only observed in the DC-CNC suspensions produced with catalyst p-toluenesulfonic acid. Scanning electron microscopy images of the cross section of DC-CNC films revealed a periodic ordered multilayer structure. DC-CNCs were also produced using recycled dicarboxylic acids.
Topics: Birefringence; Cellulose; Cotton Fiber; Dicarboxylic Acids; Gossypium; Hydrolysis; Maleates; Microscopy, Electron, Scanning; Nanoparticles; Physical Phenomena; Solubility; Solvents; Succinic Acid; Suspensions; Textiles
PubMed: 33910722
DOI: 10.1016/j.carbpol.2021.118039 -
Methods in Molecular Biology (Clifton,... 2022Azelaic acid (AzA, 1,9-nonadienoic acid) is a nine-carbon chain (C) dicarboxylic acid with multiple and diverse functions in humans and plants. In plants this compound...
Detection of Lipid Peroxidation-Derived Free Azelaic Acid, a Biotic Stress Marker and Other Dicarboxylic Acids in Tobacco by Reversed-Phase HPLC-MS Under Non-derivatized Conditions.
Azelaic acid (AzA, 1,9-nonadienoic acid) is a nine-carbon chain (C) dicarboxylic acid with multiple and diverse functions in humans and plants. In plants this compound was suggested as a marker for lipid peroxidation under biotic and abiotic stress conditions and an inducer (priming agent) of plant immunity (acquired resistance). Detection methods for AzA in plants include a wide range of methodological approaches. This new and simple reversed-phase HPLC-MS protocol describes the measurement of AzA and other dicarboxylic acids either from tobacco leaf tissue or petiolar exudates (vascular sap) of plants under non-derivatized conditions.
Topics: Biomarkers; Chromatography, High Pressure Liquid; Dicarboxylic Acids; Humans; Lipid Peroxidation; Plant Diseases; Stress, Physiological; Nicotiana
PubMed: 35657521
DOI: 10.1007/978-1-0716-2469-2_14 -
The British Journal of Dermatology Jul 1984
Review
Topics: Acne Vulgaris; Antineoplastic Agents; Dicarboxylic Acids; Humans; Melanoma; Nevus, Pigmented; Oxidation-Reduction
PubMed: 6234914
DOI: 10.1111/j.1365-2133.1984.tb04025.x -
Journal of Medicinal Chemistry May 1995The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited...
The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.
Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Dicarboxylic Acids; Dipeptides; Diuresis; Dogs; Macaca fascicularis; Male; Molecular Sequence Data; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
PubMed: 7752193
DOI: 10.1021/jm00010a014 -
Current Drug Research Reviews 2021Azelaic acid (AZA) is a white crystalline dicarboxylic acid naturally found in grains, rye, and barley. AZA has substantial biological and therapeutic abilities (viz a...
Azelaic acid (AZA) is a white crystalline dicarboxylic acid naturally found in grains, rye, and barley. AZA has substantial biological and therapeutic abilities (viz a viz) its anti-inflammatory, anti-oxidant, anti-keratinizing, anti-microbial properties, etc., which contribute to its applicability in the management of mild to harsh dermatological complications (acne, rosacea, dermatitis, hyper-pigmentation, carcinomas, etc.). AZA has shown its effectiveness against varied non-inflammatory and inflammatory lesions by normalizing hyper-keratinization state and attenuating the increased levels of microbial content. Topically AZA, either alone or in conjunction with other active moieties, has proved to effectively prevent acne and several other hyper-pigmentary conditions. Chronic applicability of AZA has been evidenced with the effects like itching, burning, stinging, redness, etc. To deal with the former issues, research is being conducted to substitute the conventional formulations with novel preparations (liposome's, niosomes, micro sponges, lipid nanocarriers, etc.), which could enhance the overall pharmaceutical and pharmacological profile of the drug. This article is an attempt to highlight the basic physiochemical properties of AZA, its physiological role (especially in dermatology), various commercial preparations and recent novel approaches that are in research with an aim to augment the therapeutic and safety profile of AZA.
Topics: Aptitude; Cosmeceuticals; Dermatologic Agents; Dicarboxylic Acids; Humans
PubMed: 34042044
DOI: 10.2174/2589977513666210526122909 -
Proteins Mar 2022Glutamate dehydrogenase (GDH) is a salient metabolic enzyme which catalyzes the NAD - or NADP -dependent reversible conversion of α-ketoglutarate (AKG) to l-glutamate;...
Glutamate dehydrogenase (GDH) is a salient metabolic enzyme which catalyzes the NAD - or NADP -dependent reversible conversion of α-ketoglutarate (AKG) to l-glutamate; and thereby connects the carbon and nitrogen metabolism cycles in all living organisms. The function of GDH is extensively regulated by both metabolites (citrate, succinate, etc.) and non-metabolites (ATP, NADH, etc.) but sufficient molecular evidences are lacking to rationalize the inhibitory effects by the metabolites. We have expressed and purified NADP -dependent Aspergillus terreus GDH (AtGDH) in recombinant form. Succinate, malonate, maleate, fumarate, and tartrate independently inhibit the activity of AtGDH to different extents. The crystal structures of AtGDH complexed with the dicarboxylic acid metabolites and the coenzyme NADPH have been determined. Although AtGDH structures are not complexed with substrate; surprisingly, they acquire super closed conformation like previously reported for substrate and coenzyme bound catalytically competent Aspergillus niger GDH (AnGDH). These dicarboxylic acid metabolites partially occupy the same binding pocket as substrate; but interact with varying polar interactions and the coenzyme NADPH binds to the Domain-II of AtGDH. The low inhibition potential of tartrate as compared to other dicarboxylic acid metabolites is due to its weaker interactions of carboxylate groups with AtGDH. Our results suggest that the length of carbon skeleton and positioning of the carboxylate groups of inhibitors between two conserved lysine residues at the GDH active site might be the determinants of their inhibitory potency. Molecular details on the dicarboxylic acid metabolites bound AtGDH active site architecture presented here would be applicable to GDHs in general.
Topics: Allosteric Regulation; Amino Acid Sequence; Aspergillus; Aspergillus niger; Catalytic Domain; Coenzymes; Dicarboxylic Acids; Enzyme Inhibitors; Glutamate Dehydrogenase; Glutamate Dehydrogenase (NADP+); Ketoglutaric Acids; Kinetics; Metabolome; NADP; Protein Binding
PubMed: 34748226
DOI: 10.1002/prot.26276